Process for the preparation of substituted pyridines via 1-aza-1,3-butadienes and the 1-aza-1,3-butadiene intermediates

ABSTRACT

Process for the preparation of substituted pyridines by allowing 1-aza-1,3-butadienes to react, in the presence of a catalytic amount of secondary amine and acid, with an aldehyde or ketone, and new 1-aza-1,3-butadienes which are used in this process. Said pyridines can be obtained in high yield in a simple process with a short reaction time. The 1-aza-1,3-butadiene can, if so desired, be prepared in situ from an imine and an aldehyde.

The invention relates to a process for the preparation of a substitutedpyridine by reaction of a 1-aza-1,3-butadiene.

A process of this type for the preparation of pyridines is disclosed byKomatsu et al. (J. Org. Chem. 49, pp. 2691-2699 (1984)). They prepareasymmetric 3,5-substituted pyridines by allowing 1 equivalent of enamineand 1 equivalent of imine to react to form a 1-aza-1,3-butadiene. Thisproduct then reacts in the course of 20-24 hours at 200° C. with anotherenamine to form an asymmetrically substituted pyridine. The yieldvaries, depending on the substituents, between 23% and 73%.

Symmetrical 3,5-substituted pyridines are prepared by allowing 2equivalents of enamine to react in the presence of acid at 200° C. for 9hours with 1 equivalent of imine. This gives pyridines in a yield,depending on the substituents, of 67 to 87%. In this case the1-aza-1,3-butadiene is formed in situ from the enamine and the imine.

This preparation process has various disadvantages, The production ofsymmetrical pyridines proceeds via a 3-step synthesis, that is to saythe synthesis of, respectively, the imine, the enamine and the pyridine.Asymmetrically substituted pyridines are prepared via a 4-stepsynthesis, that is to say synthesis of, respectively, the imine, theenamine, the 1-aza-1,3-butadiene and the pyridine. The reaction time forthe formation of the pyridine is long. The enamine is usually preparedby reaction of a secondary amine with an aldehyde. However, thispreparation frequently results in low yields, especially if the processis carried out using reactive aldehydes which are not stericallyhindered. Problems in the preparation of enamines are described, interalia, in Whitesell and Whitesell (Synthesis, July 1983, page 517-536).They give a yield of 26% for the formation of the enamine fromacetaldehyde and N-butyl-N-isobutylamine. They explain this as follows:"The low yield in the preparation of the enamine from acetaldehydedescribed above was very probably the consequence of the occurrence ofcompetitive condensation reactions and is typical of the results to beexpected in the use of reactive aldehydes which are not stericallyhindered."

In the preparation of the enamine, equivalent amounts of secondary amineand aldehyde are used. For the formation of 1 equivalent of pyridine, 2equivalents of enamine, so also 2 equivalents of secondary amine, areneeded. Since secondary amines are often expensive, it makes thereaction economically unattractive. The fact that the preparation of theenamine frequently proceeds with a low yield, as a result of which anunnecessarily large amount of secondary amine and aldehyde are consumed,does not make the reaction economically attractive either.

The object of the invention is to avoid the abovementioneddisadvantages.

This is achieved according to the invention in that a pyridine accordingto formula 1 ##STR1## where R₁ may be H or R₁ and R₃ can independentlybe chosen from (cyclo)alkyl, alkenyl, aryl, carboxyalkyl, carboxyaryl,aryloxy, alkoxy, arylthio, arylsulphonyl, NR'R" with 1-20 C-atoms, andhalogens, where R' and R" can independently be chosen from H,(cyclo)alkyl and aryl, and R₂ can be chosen from H, aryl, alkenyl, and(cyclo)alkyl with 1-20 C-atoms, and only 1 of the groups R₁ and R₂ maybe H, R₄ is chosen from H, (cyclo)alkyl, aryl, carboxyalkyl andcarboxyaryl with 1-20 C-atoms or R₃ and R₄ form together with theC-atoms to which they are attached a cycloalkyl-group with 4-8 C-atoms,is formed by allowing the 1-aza-1,3-butadiene according to formula 2##STR2## where R₅ is a OH, alkyl, aryl or alkoxy group with 1-20 C-atomsand R₁ and R₂ have the meaning described above, to react, in thepresence of a catalytic amount of secondary amine and acid, with analdehyde or ketone according to formula 3 ##STR3## where R₃ and R₄ havethe meaning described above.

R₁, R₂, R₃ and R₄ usually contain 1-20 C atoms and may optionally besubstituted. Possible substituents on R₁, R₂, R₃ and R₄ are, forexample, halogen, --OH, --SH, (cyclo)alkyl, aryl, aryloxy, alkoxy,carboxyalkyl, carboxyaryl, NO₂, SO₂ and NR'R", where R' and R" canindependently be chosen from H, alkyl and aryl. R₅ is usually an alkylor aryl group having 1-20 C atoms, such as, for example, tertiary butyl,isopropyl and benzyl, tertiary butyl being preferred, or an hydroxygroup or an alkoxy group with 1-20 C atoms which may be unsaturated oraromatic such as for example (chloro)allyl.

The molar ratio of 1-aza-1,3-butadiene to aldehyde or ketone which isused in this reaction is not critical and is preferably between 1:1 and1:3.

Symmetrically substituted pyridines according to formula 4 ##STR4## canbe formed by allowing the imine according to formula 5 ##STR5## where R₂and R₅ have the abovementioned meaning, to react, in the presence of acatalytic amount of secondary amine and acid, with an aldehyde accordingto formula 3, where R₄ is hydrogen and R₃ has the abovementionedmeaning. It is assumed that the 1-aza-1,3-butadiene is formed in situand immediately further reacts to give a symmetrically substitutedpyridine. The invention also relates to this direct process of preparingsymmetrical pyridines.

The 1-aza-1,3-butadiene can also be prepared by allowing an amine R₅--NH₂ wherein R₅ has the above mentioned meaning to react with an alpha,beta-unsaturated aldehyde according to formula 6 ##STR6## where R₁ andR₂ have the abovementioned meaning, with the proviso that when R₅represents an alkyl or aryl group R₂ is not H. After the addition of analdehyde or ketone according to formula 3 and a catalytic amount ofsecondary amine and acid, pyridines are formed. The reaction withketones is preferentially performed with amines with R₅ is hydroxy oralkoxy.

The ratio between the various reactants can vary. If formation ofsymmetrical pyridines from 1-aza-1,3-butadiene formed in situ is optedfor, a minimum of 2 equivalents of the aldehyde according to formula 3per equivalent of imine according to formula 5 is needed, on the basisof the reaction mechanism, to achieve optimum results. Preferably,between 2 and 4 equivalents are added.

The amount of secondary amine can be chosen within wide limits. It hasbeen found that higher concentrations of secondary amine usually producehigher yields. However, secondary amines are frequently expensive. Whendetermining the amount of secondary amine, economic considerations alsoplay a role, in addition to yield considerations, Preferably, the molarratio of aldehyde:secondary amine is chosen between 5:1 and 15:1. Manysecondary amines are suitable for use as catalyst. Cyclic amines, inparticular piperidine, are preferred.

The choice of the acid is not critical. Suitable acids are, for example,inorganic acids, carboxylic acids or sulphonic acids, such ashydrochloric acid, acetic acid and p-toluenesulphonic acid. The molarratio of amine:acid can vary within wide limits and is usually chosenbetween 0.4 and 50.

If the 1-aza-1,3-butadiene is prepared from an amine and analpha,beta-unsaturated aldehyde, the molar ratio of amine:unsaturatedaldehyde is generally chosen around 1:1. Usually, a small excess ofamine (between 1.0 and 1.2 equivalents per equivalent of the unsaturatedaldehyde) is added. In theory, equal amounts of 1-aza-1,3-butadiene andaldehyde or ketone are needed for the formation of the pyridine from1-aza-1,3-butadiene and aldehyde or ketone. In practice, an excess ofaldehyde or ketone is usually added.

The reaction temperature can vary within wide limits. Usually saidtemperature is chosen between 100 and 300° C. A reaction temperaturebetween 180 and 220° C. is preferred. In this temperature range thereaction is complete within 2 hours in virtually all cases.

It has been found that the process according to the invention providesthe following advantages. Substituted pyridines can be prepared in asimpler process, with fewer reaction steps, by direct use of the readilyaccessible aldehyde or ketone, instead of the enamine, which issometimes difficult to prepare. As a result, only a catalytic amount ofsecondary amine is required. Moreover, the overall yield relative to thealdehyde or ketone increases appreciably. The reaction time for thepyridine formation is appreciably reduced.

A number of pyridines occur in natural products. The invention providesa process with which substituted pyridines, some of which are new, canbe prepared in a simple manner. These pyridines can be used in variousfields.

Alkylpyridines can, for example, be used as precursors forpyridinemonocarboxylic and -dicarboxylic acids, which show a directrelationship with nicotine derivatives.

The invention also relates to the new compounds having the generalformula ##STR7## where R₁ is H and R₂ is ethyl, isopropyl, n-butyl,(cyclo)alkyl having 5-20 C atoms, alkoxy having 1-20 C atoms, athioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C oratoms phenyl substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms,halogen, or where R₂ is H and R₁ is n-propyl, alkyl having 4-20 C atoms,alkoxy having 2-20 C atoms, thioalkyl, alkylamino or arylamino grouphaving 1-20 C atoms or phenyl optionally substituted with hydroxy,(cyclo)alkyl having 1-5 C atoms, alkoxy having 1-5 C atoms, halogen, orwhere R₁ and R₂ each independently represent (cyclo)alkyl having 4-20 Catoms, alkoxy having 2-20 C atoms, halogen, a thioalkyl, thioaryl,alkylamino or arylamino group having 1-20 C atoms or phenyl optionallysubstituted with hydroxy, (cyclo)alkyl having 1-5 C atoms, alkoxy having1-5 C atoms, halogen and the new compounds having the general formula##STR8## where R₁ is H and R₂ is (cyclo)alkyl having 2-20 C atoms,alkenyl having 3-20 C atoms, alkoxy having 1-20 C atoms, a thioalkyl,thioaryl, alkylamino or arylamino group having 1-20 C atoms or phenylsubstituted with hydroxy, (cyclo)alkyl having 1-5 C atoms, alkoxy having2-5 C atoms, halogen or where R₂ is H and R₁ is (cyclo)alkyl having 2-20C atoms, alkoxy having 2-20 C atoms, alkenyl having 2-20 C atoms, athioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C atomsor phenyl optionally substituted with hydroxy, (cyclo)alkyl having 1-5 Catoms, alkoxy having 1-5 C atoms, halogen or where R₁ and R₂ eachindependently represent (cyclo)alkyl having 2-20 C atoms, alkoxy having1-20 C atoms, alkenyl having 2-20 C atoms, halogen, a thioalkyl,thioaryl, alkylamino or arylamino group having 1-20 C atoms or phenyloptionally substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms,alkoxy having 1-5 C atoms, halogen, and the new compounds having thegeneral formula ##STR9## where R₁ is H and R₂ is (cyclo)alkyl having2-20 C atoms, alkenyl having 5-20 C atoms, alkoxy having 1-20 C atoms athioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C atomsor phenyl substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms,alkoxy having 1-5 C atoms, halogen or in which R₂ is H and R₁ is(cyclo)alkyl having 3-20 C atoms, alkenyl having 2-7 C atoms, alkoxyhaving 1-20 C atoms, a thioalkyl, thioaryl, alkylamino or arylaminogroup having 1-20 C atoms or phenyl optionally substituted with hydroxy,(cyclo)alkyl having 1-5 C atoms, alkoxy having 1-5 C atoms, halogen orwhere R₁ and R₂ each independently represent (cyclo)alkyl having 3-20 Catoms, alkenyl having 2-20 C atoms, alkoxy having 1-20 C atoms, athioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C atomsor phenyl optionally substituted with hydroxy, (cyclo)alkyl having 1-5 Catoms, alkoxy having 1-5 C atoms, halogen, and the new compounds havingthe general formula ##STR10## where R₁ is H and R₂ is (cyclo)alkylhaving 2-20 C atoms, alkenyl having 2-20 C atoms, alkoxy having 1-20 Catoms, halogen, a thioalkyl, thioaryl, alkylamino or arylamino grouphaving 1-20 C atoms or phenyl substituted with hydroxy, (cyclo)alkylhaving 1-5 C atoms, alkoxy having 1-5 C atoms, halogen, with the provisothat phenyl is not substituted in the p-position with methyl, isopropyl,methoxy, Cl or Br, or where R₂ is H and R₁ is (cyclo)alkyl having 3-20 Catoms, alkoxy having 1-20 C atoms, alkenyl having 2-20 C atoms, halogen,a thioalkyl, thioaryl, alkylamino or arylamino group having 1-20 C atomsor phenyl optionally substituted with hydroxy, (cyclo)alkyl having 1-5 Catoms, alkoxy having 1-5 C atoms, halogen, or where R₁ and R₂ eachindependently represent (cyclo)alkyl having 2-20 C atoms, alkenyl having2-20 C atoms, alkoxy having 1-20 C atoms, halogen, a thioalkyl,thioaryl, alkylamio or arylamino group having 1-20 C atoms or phenyloptionally substituted with hydroxy, (cyclo)alkyl having 1-5 C atoms,alkoxy having 1-5 C atoms, halogen with the proviso that R₁ and R₂ arenot at the same time given by R₁ =C₂ H₅ or C₃ H₇ and R₂ = a phenylgroupin the p-position substituted with CH₃, OCH₃, F, Cl or Br, and the newcompounds having the general formula ##STR11## where R is (cyclo)alkylwith 1-20 C atoms and R₁ and R₂ each independently represent H,(cyclo)alkyl having 1-20 C atoms, alkoxy having 1-20 C atoms, alkenylhaving 2-20 C atoms, halogen a thioalkyl, thioaryl, alkylamino orarylamino group having 1-20 C atoms or phenyl optionally substitutedwith hydroxy, (cyclo)alkyl having 1-5 C atoms, alkoxy having 1-5 Catoms, halogen, with the proviso that R, R₁ and R₂ are not at the sametime given by R is H and R₂ is phenyl or phenyl in the p-positionsubstituted with methyl, methoxy or halogen, or R is CH₃, R₁ is CH₃ andR₂ is phenyl; These compounds are formed as an intermediate in theprocess according to the invention.

Alkyl, alkenyl or aryl groups may optionally be substituted with theabovementioned substituents.

The invention is further elucidated by means of the following examples,without being restricted by these.

The NMR data are given as follows. The shift is indicated in ppmdownfield with respect to TMS. The multiplicity is indicated as s(singlet), d (doublet), t (triplet), q (quartet), sept. (septet), m(multiplet) and b (broad signal). Aromatic protons are given as pyr.(protons on pyridine ring) and Ph. (protons on phenyl ring).

EXAMPLE I Preparation of 1-tert-butyl-4-phenyl-1-aza-1,3-butadiene

20.3 grams of t-butylamine (0.28 mol) was metered over a period of 16minutes to 33.0 grams of cinnamaldehyde (0.25 mol) during stirring andcooling. The mixture was left to stand overnight at room temperature.150 ml of butanone was then added to the crude reaction mixture toenable the water formed during the reaction to be evaporatedazeotropically. The mixture was evaporated on a rotary evaporator. Theresidue consisted of 45.6 grams of product having a purity of 98%. Yield96%.

¹ H NMR: δ=1.29 ppm, s, 9H, 3 CH₃ δ=6.80 ppm, s (b), and δ=6.89 ppm, s(b), 2H, 2CH═δ=7.10-7.55 ppm, m, 5H, Ph. δ=7.93 ppm, t, 1H, CH═N

Preparation of 3-methyl-4-phenylpyridine, from1-tert-butyl-4-phenyl-1-aza-1,3-butadiene and propanal

3.7 grams (20 mmols) of the 1-aza-1,3-butadiene prepared above, 3.5grams of propanal (60 mmols), 0.7 gram of piperidine (8.2 mmols), 4.4grams of toluene (solvent) and 1.0 gram of a solution of 1.2 grams ofacetic acid in 48.8 grams of toluene (0.4 mmol of acetic acid) wereadded together in a Cr-Ni steel autoclave with a capacity of about 15ml. The latter was heated for 2 hours in an oil bath at a temperature of200° C. After 2 hours the reaction mixture was cooled in air. The notoptimized yield of 3-methyl-4-phenylpyridine was 34% (GC analysis). Thereaction mixture was purified by means of a fractional distillation, bywhich means product having a purity of 86% was obtained. Furtherpurification took place by dissolving the distillate in hexane and bypassing HCl gas through this solution, as a result of which the pyridineHCl salt precipitated. The salt was filtered off. A dilute sodiumhydroxide solution was then added, after which the aqueous solution wasextracted with dichloromethane. After evaporating off thedichloromethane, product having a purity of 98.8% was obtained.

¹ H NMR: δ=2.23 ppm, s, 9H, 3 CH₃ δ=7.03 ppm, d, 1H, pyr. δ=7.1-7.5 ppm,m (b), 5H, Ph. δ=8.38 ppm, d, 2H, pyr.

EXAMPLE II Preparation of the imine of t-butylamine and formaldehyde(t-butylmethyleneimine as triazine trimer)

295.0 grams of t-butylamine (4.0 mols) was metered to 120.0 grams ofparaformaldehyde (4.0 mols), with cooling. 1/3 of the amine was added ina single amount. The stirrer was then started. The remainder of theamine was added over a period of 11/4 hours, after which the mixture wasstirred for a further 1/2 hour at room temperature. The crude reactionmixture was transferred to a separating funnel, in which said mixtureseparated in the course of about 2 hours into an aqueous phase and aturbid organic phase. The organic phase was filtered through filterearth. The clear filtrate, 327.6 grams, consisted of 98% pure imine (inthe form of triazine trimer). Yield 94%.

Preparation of 3,5-dimethylpyridine from t-butylmethyleneimine andpropanal

211.8 grams of the t-butylmethyleneimine prepared above (98% pure, 2.44mols), 424.5 grams of propanal (7.32 mols), 292.8 grams of toluene(solvent), 76.1 grams of piperidine (0.9 mol) and 103.6 grams of aceticacid (1.73 mols) were mixed with cooling in an ice/water bath whilebeing stirred. Piperidine and acetic acid were added in small portionsin connection with the release of heat. The mixture was transferred toan autoclave and heated at 200° C. for 3 hours (heating-up time about 45min.). The reaction mixture was cooled to room temperature. It was thenwashed with 400 grams of a 20% (wt) NaOH solution in water. The aqueousphase contained no 3,5-dimethylpyridine. The organic phase contained100.0 grams of product (not optimized yield 38.3%). The volatilecomponents were distilled off from the organic phase under atmosphericpressure through a column having 20 actual plates. The residue wasdistilled under vacuum through a column having 20 actual plates. Thisresulted in 78.9 grams of 3,5-dimethylpyridine having a purity of 98%(distillation yield 79%, overall yield 30.2%). Boiling point 104°-107°C. (102 mm Hg). In this case the 1-aza-1,3-butadiene was formed in situfrom the imine and the aldehyde, after which the pyridine formation tookplace.

¹ H NMR: δ=2.28 ppm, s, 6H, 2 CH₃ δ=7.23 ppm, m, and δ=8.75 ppm, m, 3H,pyr.

EXAMPLE III Preparation of 3,5-dimethylpyridine fromt-butylmethyleneimine and propanal

1.7 grams of the t-butylmethyleneimine prepared in Example II (20mmols), 3.5 grams of propanal (60 mmols), 0.8 gram of piperidine (9.4mmols), 6.1 grams of toluene (solvent) and 1.0 gram of a solution of 1.2grams of acetic acid in 48.8 grams of toluene (0.4 mmol of acetic acid)were added together in a Cr--Ni steel autoclave with a capacity of about15 ml. The latter was heated for 2 hours in an oil bath at a temperatureof 200° C. After 2 hours the reaction mixture was cooled in air. Theyield of 3,5-dimethylpyridine was 50% (GC analysis).

EXAMPLE IV Preparation of 3,5-diethylpyridine from t-butylmethyleneimineand butanal

1.7 grams of the t-butylmethyleneimine (20 mmols) prepared in ExampleII, 4.3 grams of butanal (60 mmols), 0.7 gram of piperidine (8.2 mmols),5.6 grams of toluene (solvent) and 1.0 gram of a solution of 1.2 gramsof acetic acid in 48.8 grams of toluene (0.4 mmol of acetic acid) wereadded together in a Cr--Ni steel autoclave with a capacity of about 15ml. The latter was heated for 2 hours in an oil bath at a temperature of200° C. After 2 hours the reaction mixture was cooled in air. The notoptimized yield of 3,5-diethylpyridine was 55% (GC analysis). The crudeproduct was purified by means of vacuum distillation. Boiling point86°-88° C. (10 mm Hg), purity 84%. Further purification took place byprecipitating the distilled product as the HCl salt in hexane. The saltwas filtered off and then dissolved in water and the solution wasneutralised using 33% strength by weight NaOH solution in water. Theaqueous solution was then extracted with dichloromethane. This resultedin a product having a purity of 98.5%.

¹ H NMR: δ=1.20 ppm, t, 6H, 2 CH₃ δ=2.58 ppm, q, 4H, 2 CH₂ δ=7.20 ppm,t, and 8.18 ppm, d, 3H, pyr.

EXAMPLE V Preparation of 3,5-di-isopropylpyridine fromt-butylmethyleneimine and isovaleraldehyde

1.7 grams of t-butylmethyleneimine (20 mmols), 5.2 grams ofisovaleraldehyde (60 mmols), 0.7 gram of piperidine (8.2 mmols), 4.7grams of toluene (solvent) and 1.0 gram of a solution of 1.2 grams ofacetic acid in 48.8 grams of toluene (0.4 mmol of acetic acid) wereadded together in each of 4 Cr--Ni steel autoclaves with a capacity ofabout 15 ml. The latter were heated for variable periods in an oil bathat a temperature of 200° C. The reaction mixtures were then cooled inair. The not optimized yield was 47% after 1 hour, 51% after 2 hours,53% after 3 hours and 56% after 4 hours (GC analysis). The crude productwas purified by means of distillation, which resulted in a number offractions having a 3,5-di-isopropylpyridine content which varied between10 and 80%. The 3,5-di-isopropylpyridine crystallized out in thefractions having a content higher than 38%. Product having a purity of93% was obtained by filtering off.

Melting point 36.5°-38.5° C. ¹ H NMR: δ=1.25 ppm, d, 12H, 4 CH₃ δ=2.88ppm, sept., 2H, 2 CH δ=7.28 ppm, t, and 8.20 ppm, d, 3H, pyr.

EXAMPLE VI Preparation of the imine of t-butylamine and benzaldehyde

36.0 grams (0.5 mol) of t-butylamine was metered to 52.2 grams ofbenzaldehyde (0.5 mol) over a period of 60 minutes during stirring.After all of the t-butylamine had been added, the mixture was stirredfor a further 1 hour at room temperature. A further 14.6 grams (0.2 mol)of t-butylamine was then added, after which the mixture was stirred for11/2 hours at room temperature. The reaction mixture was transferred toa separating funnel and 100 ml of diethyl ether was added to allowbetter separation of the organic and the aqueous phase. The organiclayer was dried over MgSO₄. The latter was filtered off. The filtratewas evaporated in a rotary evaporator. This yielded 65.0 grams ofproduct having a purity of 99%. Yield 82%.

¹ H NMR: δ=1.34 ppm, s, 9H, 3 CH₃ δ=7.18-7.40 ppm, m, and 7.56-7.78 ppm,m, 5H, Ph. δ=8.16 ppm, s, 1H, CH═N

Preparation of 3,5-diphenylpyridine from t-butylmethyleneimine andphenylacetaldehyde

10.3 grams of the t-butylmethyleneimine prepared above (98% pure; 0.12mols), 51.0 grams of phenylacetaldehyde (85% pure; 0.36 mols), 13.4grams of toluene (solvent), 4.52 grams of piperidine (0.053 mols) and0.20 grams of acetic acid (0.003 mols) were mixed with cooling in anice/water bath while being stirred. The mixture was transferred to anautoclave and heated at 200° C. for 11/2 hours. After cooling toroomtemperature the separated crystals were filtered and washed withsuction. After drying of the solid 19.0 grams of 98% pure3,5-diphenylpyridine was obtained (The yield was 68% without anyoptimization). In this case the 1-aza-1,3-butadiene was formed in situfrom the imine and the aldehyde, after which the pyridine formation tookplace.

¹ H NMR: δ=7.4-7.7 ppm, m, 10H, 2 Ph δ=8.05 ppm, t, 1H, 4-H δ=8.83 ppm,d, 2H, 2-H and 6-H

EXAMPLE VII Preparation of formaldoxime (as trimer)

64.2 grams of a solution of NaOH in water (50%; 0.802 mols) was added toa stirred solution of 66.1 grams of hydroxylamine sulfate (0.805 mols)in 134.1 grams of water with cooling (t ≃25° C.). Then, a solution of22.2 grams of formaldehyde (0.74 mols) in 37.8 grams of water was added,immediately followed by the addtion of 100 ml of ether. After separationof the two layers, the water phase was extracted 3 times with ether. Thecombined organic phases were dried (CaCl₂) and the solvent wasevaporated in vacuum. The residue (30.0 grams) consisted of 97% pureformaldoxime (in the form of its trimer). Yield: 87%.

Preparation of 3,5-dimethylpyridine from formaldoxime and propanal

6.3 grams of the formaldoxime prepared above (97% pure; 0.14 mols), 23.2grams of propanal (0.4 mols), 52.2 grams of toluene (solvent), 5.24grams of piperidine (0.062 mols) and 0.36 grams of piperidine. HCl salt(0.003 mols) were mixed with cooling in an icewater both while beingstirred. The mixture was transferred to an autoclave and heated at 200°C. for 11/2 hours. After cooling to room temperature the reactionmixture was analyzed. The not optimized yield of 3,5-dimethylpyridinewas 26% (GC analysis).

EXAMPLE VIII Preparation of cinnamaldehyde oxime

53.3 grams of cinnamaldehyde (0.40 mols) was added to a solution of 39.1grams of hydroxylamine sulfate (0.48 mols) in 79.5 grams of water. Themixture was cooled in an icewater bath to 3° C. Then a solution of 17.7grams of NaOH (0.44 mol) in 17.7 grams of water was added over a periodof 25 minutes. The formed cinnamaldehyde oxime precipitated. Thereaction mixture was warmed to roomtemperature and the crude product wasfiltered. After recrystallization from toluene pure cinnamaldehyde oximewas obtained as white crystals. Yield: 70%.

Preparation of 4-phenyl-5,6,7,8-tetrahydroquinoline

13.9 grams of the cinnamaldehyde oxime prepared according to the abovedescribed procedure (0.09 mols), 28.5 grams of cyclohexanon (0.29 mols),30.3 grams of toluene (solvent), 3.44 grams of piperidine (0.040 mols)and 0.259 grams of piperidine. HCl salt (0.002 mols) were mixed withcooling in an icewater bath while being stirred. The mixture wastransferred to an autoclave and heated at 200° C. for 11/2 hours. Aftercooling to room temperature the mixture was analyzed. The not optimizedyield of 4-phenyl-5,6,7,8-tetrahydroquinoline was 34% (GC-analysis).

EXAMPLE IX Preparation of methacroleine oxime

32.7 grams of hydroxylamine hydrochloride (0.47 mols) was dissolved in66.4 grams of water. This solution was cooled in an icewater bath to3°-5° C. and 32.0 grams of methacroleine (0.45 mols) was added withstirring. Subsequently 35.7 grams of a solution of NaOH in water (50%;0.45 mol) was added at 4° C. over a period of 1 hour. Then the reactionmixture was brought at room temperature and extracted with ether. Thecombined organic phases were dried (MgSO₄) and the solvent was removedunder reduced pressure. The residue (36.7 grams) consisted of puremethacroleine oxime (93% in ether); Yield: 89%.

Preparation of 3,5-dimethylpyridine from methacroleine oxime andpropanal

13.0 grams of the methacroleine oxime prepared according to the abovedescribed procedure (93% in ether; 0.14 mol), 22.0 grams of propanal(0.38 mols), 46.5 grams of toluene (solvent), 4.93 grams of piperidine(0.058 mols) and 0.35 grams of piperidine. HCl salt (0.003 mols) weremixed with cooling in an icewater bath while being stirred. The mixturewas transferred to an autoclave and heated at 200° C. for 11/2 hours.After cooling to room temperature the mixture was analysed. The notoptimalized yield of 3,5-dimethylpyridine was 28% (GC-analysis).

EXAMPLE X Preparation of 3,5-dimethylpyridine from O-methylformaldoximeand propanal

8.3 grams of O-methylformaldoxime (0.14 mols), prepared according to theprocedure of Jensen et al. (Acta Chem. Scand., 31, 28 (1977), 23.2 gramsof propanal (0.40 mols) 52.2 grams of toluene (solvent), 5.33 grams ofpiperidine (0.063 mols) and 0.18 grams of acetic acid (0.003 mols) weremixed with cooling in an icewater bath while being stirred. The mixturewas transferred to an autoclave and heated at 200° C. for 11/2 hours.After cooling to room temperature the reaction mixture was analysed. Thenot optimized yield of 3,5-dimethylpyridine was 28% (GC analysis).

We claim:
 1. A process for the preparation of a substituted pyridine byreaction of a 1-aza-1,3-butadiene wherein, a pyridine represented byformula 1 ##STR12## wherein R₁ is H or R₁ and R₃ can be a 1-20 carbonatom group independently selected from the group consisting of(cyclo)alkyl, aryl, and alkoxy and R₂ is H or a 1-20 carbon atom groupindependently selected from the group consisting of aryl and(cyclo)alkyl, wherein only one of R₁ and R₂ may be H, R₄ is selectedfrom the group consisting of H, aryl having 6 to 20 carbon atoms and(cyclo)alkyl with 1-20 carbon atoms, or R₃ and R₄ form together with theC atoms to which they are attached a cycloalkyl group with 4-8 C-atoms,is formed by allowing an 1-aza-1,3-butadiene represented by formula (2)##STR13## wherein R₅ is a OH, alkyl having 1-20 carbon atoms, arylhaving 6-20 carbon atoms or alkoxy group having 1-20 C-atoms and R₁ andR₂ have the meaning described above, to react, in the presence of acatalytic amount of secondary amine and acid, with an aldehyde or ketonerepresented by formula (3) ##STR14## wherein R₃ and R₄ have the meaningdescribed above.
 2. A process according to claim 1, wherein the processis conducted at a molar ratio of 1-aza-1,3-butadiene:aldehyde or ketoneof between 1:1 and 1:3.
 3. A process according to claim 1, wherein R₁ isindependently selected from group consisting of hydrogen, methyl, ethyl,isopropyl and phenyl.
 4. A process according to claim 1, wherein R₃ isindependently selected form the group consisting of methyl, ethyl,isopropyl and phenyl.
 5. A process according to claim 1, wherein thereaction is conducted at a temperature of 100° C. to 300° C.
 6. Aprocess according to claim 1, wherein the reaction is conducted at atemperature of 180° C. to 220° C.
 7. A process according to claim 1,wherein the acid is a carboxylic acid or sulphonic acid.
 8. A processaccording to claim 1, wherein the acid is selected from the groupconsisting of hydrochloric acid, acetic acid and p-toluenesulphonicacid.
 9. A process according to claim 1, wherein the secondary amine hasa cyclic structure.
 10. A process according to claim 1, wherein thesecondary amine is piperidine.
 11. A process for the preparation of asymmetrical pyridine represented by formula 4: ##STR15## wherein R₃ is a1-20 carbon group selected from the group consisting (cyclo)alkyl, aryl,alkoxy, R₂ is selected from the group consisting of H, aryl having 6 to20 carbon atoms, and (cyclo)alkyl with 1-20 C-atoms, wherein an iminerepresented by formula 5: ##STR16## wherein R₂ has the above-mentionedmeaning and % is an OH, alkyl having 6 to 20 carbon atoms, aryl having 6to 20 carbon atoms or alkoxy group with 1-20 C-atoms, is allowed toreact, in the presence of a catalytic amount of a secondary amine and anacid, with an aldehyde represented by formula (3) ##STR17## wherein R₃has the above-mentioned meaning.
 12. A process according to claim 11,wherein the process is conducted at a molar ratio of imine:aldehyde ofbetween 1:2 and 1:4.
 13. A process according to claim 11, wherein thesecondary amine has a cyclic structure.
 14. A process according to claim11, wherein the processes conducted at a temperature between 100° C. and300° C.
 15. A process according to claim 11, wherein the temperature isbetween 180° C. and 220° C.
 16. A process according to claim 11, whereinthe acid is a carboxylic acid or sulphonic acid.
 17. A process accordingto claim 11, wherein the acid is selected from the group consisting ofhydrochloric acid, acetic acid and p-toluenesulphonic acid.
 18. Aprocess according to claim 11, wherein the secondary amine ispiperidine.
 19. A process according to claim 1, wherein R₅ is hydroxylor methoxy.